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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that angiotensin II (AII) is a mitogen for neonatal rat cardiac fibroblasts. However, the signaling events that lead to fibroblast cell growth in response to AII remain to be elucidated. Mitogen-activated protein (MAP) kinases are cytosolic serine/threonine kinases which have been shown to be activated in quiescent cells by diverse growth stimuli, thereby being linked to growth regulatory pathways. This study was designed to determine whether MAP-kinase activation occurred in response to AII/receptor coupling in neonatal rat cardiac fibroblasts and the role of MAP-kinase activation in the AII-induced proliferation of these cells. Immunoblot analysis of MAP-kinase isoforms revealed predominantly p44 with less p42 MAP-kinase in rat cardiac fibroblasts. Both isoforms were activated upon stimulation of the cells with AII for 5 min or platelet derived growth factor-BB for 10 min. Angiotensin II stimulated MAP-kinase in a dose-dependent fashion with an EC50 of 2.5 nM. Two minutes following stimulation with 1 microM AII MAP-kinase activity increased from 90 +/- 17.9 to 477.5 +/- 75.9 pmol/min/mg protein, P < 0.05, n = 4. A smaller, sustained, secondary increase in MAP-kinase activity from 37.7 +/- 5.3 to 110.9 +/- 15.3 pmol/min/mg protein, P < 0.05, n = 4, was observed in response to AII between 120-150 minutes following receptor occupancy. The responses to AII were markedly attenuated by the AT1 receptor antagonist EXP3174. Stimulation of the cells with carbachol induced the first but not the second phase of MAP-kinase activity and this compound had no effect on cellular growth. The second phase of MAP-kinase activity 2-2.5 h after AII stimulation, paralleled data demonstrating that a 2-3 h receptor occupancy with AII was necessary to induce DNA synthesis and fibroblast proliferation. These results indicate that AII stimulates a biphasic activation of MAP-kinase by the AT1 receptor and that this pathway may participate in the AII induced mitogenic response in cardiac fibroblasts.
J Mol Cell Cardiol 1995 May
PMID:Angiotensin II is a potent stimulator of MAP-kinase activity in neonatal rat cardiac fibroblasts. 747 73

In hypertensive heart disease, after myocardial infarction or in congestive heart failure, myocardial fibrosis presenting as a diffuse perivascular and interstitial accumulation of fibrillar collagens within the normal connective tissue structures of the myocardium is associated with an activated renin-angiotensin system (RAS). This reactive fibrosis occurs in the overloaded left ventricle and the nonoverloaded right ventricle irrespective of myocyte necrosis or the development of myocyte hypertrophy. Therefore, it appears that hemodynamic factors or the load of the ventricle are not primarily responsible for the adverse fibrous tissue response in the myocardium, and humoral factors may play a key role in regulating the myocardial collagen matrix. The neurohumoral response in hypertensive heart disease, after myocardial infarction with overall deterioration of left ventricular function or congestive heart failure leads to an activation of either the cardiac or the circulating RAS, which closely interacts with the bradykinin-prostaglandin system. To ascertain whether the RAS modulates collagen fibroblasts that express mRNAs for types I and III collagens (the major fibrillar collagens in the heart) and matrix metalloproteinase 1 (MMP1; the key enzyme for collagen degradation), collagen synthesis was measured by [3H]proline incorporation normalized to total protein synthesis and MMP1 activity was determined by degradation of [14C]collagen in cultured fibroblasts after 24-hour incubation with various concentrations of angiotensin II or PGE2 (10(-11)-10(-3) M) under serum-free conditions. In addition, effects of angiotensin II were evaluated in the presence or absence of either type 1 (ICI D8731) or type 2 (PD 123177) angiotensin II (AT1 or PGE2 (10(-11)-10(-3) M) under serum-free conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Cardiol 1995 Nov 02
PMID:Role of angiotensin II and prostaglandin E2 in regulating cardiac fibroblast collagen turnover. 749 21

We have proposed that ischemic preconditioning in the rabbit heart is initiated by adenosine A1 receptor stimulation which results in an upregulation of protein kinase C (PKC). Subsequent sustained ischemia then causes renewed stimulation of adenosine A1 receptors with rapid reactivation of PKC and phosphorylation of a target protein(s) which mediates the protection. If the above theory is correct then angiotensin II (AII) receptor stimulation, which is known to activate PKC, should also protect the heart. Isolated rabbit hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Infarct size was determined by tetrazolium staining. Pretreating hearts with 100 mM AII for 5 min, followed by 10 min of drug-free perfusion prior to the prolonged ischemia limited infarction (7.2 +/- 2.0% of the risk area v 31.1 +/- 3.4% in control animals, P < 0.01). This protection could be blocked by the AT1 receptor blocker losartan (10 microM), but not by the AT2 receptor blocker PD 123319 (10 microM). Polymyxin B (50 microM), a PKC inhibitor, also blocked the protective effect of AII. These observations demonstrated that activation of PKC by AT1 receptor stimulation prior to ischemia does mimic ischemic preconditioning. Following AII infusion, administration, during the 30 min ischemic period, of either SPT [8-(p-sulfophenyl)theophylline] (an adenosine receptor blocker) or losartan failed to block AII's protective effect. However, co-administration of SPT and losartan did abort AII's protection suggesting that AII may not be completely washed out during the 10 min drug-free perfusion allowing residual agonist to reactivate PKC during the 30 min ischemia even when adenosine receptors are blocked. Thus, if only one of the receptors (AT1 or adenosine) were activated during the ischemic period, protection would occur. We conclude that activation of PKC by AII, prior to ischemia, can limit myocardial infarction. While PKC must be reactivated during ischemia to realize protection, the specific receptor type initiating reactivation is not crucial.
J Mol Cell Cardiol 1995 Mar
PMID:Pretreatment with angiotensin II activates protein kinase C and limits myocardial infarction in isolated rabbit hearts. 760 6

Antihypertensive drug therapy can lower blood pressure and prolong life, but many hypertensive patients continue to develop further risk factors and to die prematurely of heart disease. Antihypertensive drugs can also interfere with the patient's quality of life, and many are not compatible with the concomitant medical conditions of the patient and the medications taken to treat them. For these reasons, the antihypertensive therapy selected should meet the specific and complete needs of each patient, not just treat the high blood pressure. An analysis of the drugs that inhibit the renin-angiotensin system suggests that several of these drugs have a more favorable therapeutic profile than other classes of hypotensive agents. The newly developed receptor-site-specific blockers are expected to be tolerated better by hypertensive patients and, consequently, to enhance their quality of life. The first of the new class of nonpeptide blockers of the AT1 receptor, losartan--which has no partial agonist activity--is likely to have the advantages of the angiotensin-converting enzyme inhibitors without their adverse effects, notably cough. In selected patients, the AT1-receptor blockers could become the drugs of first choice for the management of hypertension.
Clin Cardiol 1995 Jun
PMID:Antihypertensive therapy targeted to the needs of the patient: focus on the renin-angiotensin system; older and newer agents. 763 60

The renin-angiotensin system is critical for regulating extracellular fluid volume and blood pressure. Angiotensin II, the active peptide hormone produced by the renin enzymatic cascade, sustains vascular volume and blood pressure by constricting vessels, stimulating adrenal aldosterone secretion, increasing renal tubular sodium absorption, activating the sympathetic nervous system, and increasing cardiac contractility. These actions are a disability in the pathophysiologic states of hypertension and congestive heart failure (CHF), however, since reactive increases in renal renin and angiotensin II stimulate sympathetic activity and renal sodium retention, leading consequently to circulatory volume over-load. The actions of angiotensin II are mediated by its interactions with specific cell-surface angiotensin II receptors, namely, AT1 and AT2; most cardiovascular actions of angiotensin II come from its interaction with the AT1 receptor. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II-receptor blockers antagonize the actions of the renin-angiotensin axis, neutralizing its effects on hypertension and heart failure. Losartan is the first oral, nonpeptide, selective AT1-receptor blocker to be approved. Clinical trials show it to be effective and well tolerated as therapy for hypertension and CHF. Data obtained thus far suggest ACE inhibitors and AT1-receptor blockers have similar efficacy for treating these conditions, but the receptor blockers appear to produce fewer adverse effects. Whether the sustained increase in angiotensin II concentrations after AT1-receptor antagonism produces deleterious effects is not known. The concern is that these high levels may stimulate unblocked AT2 receptor; the effect of that stimulation may not be important, however.
Clin Cardiol 1995 Jun
PMID:Angiotensin receptors: physiology and pharmacology. 763 61

Angiotensin II (Ang II) is an essential component of the renin-angiotensin system and is partially responsible for the maintenance of hypertension. Two major receptor subtypes have been defined for Ang II and have been detected in the heart of various species. Most of the known functions of Ang II are mediated via the AT1 subtype, whereas the function of the AT2 receptor remains ill defined. In this study we aimed to localize both receptor subtypes in the rabbit heart using film and light microscope autoradiography as well as radioligand binding assays on membranes. Total receptor densities in the atrium and nervous tissue were respectively four and nine times greater than in the ventricle. Conductive tissue shows a density between that of atrial and nervous tissue. In the ventricle, approximately 20% of the Ang II receptors were AT2. This receptor subtype was almost totally absent from nervous, conductive and atrial tissue. The limited resolution of the microscope autoradiography method did not allow us to specify the exact cell-type at this stage.
J Mol Cell Cardiol 1995 Jan
PMID:Localization of angiotensin II receptor subtypes in the rabbit heart. 776 Mar 66

The distribution and function of AII receptor subtypes was evaluated in different preparations of rat hearts. Autoradiographic experiments and binding experiments on isolated membranes showed a large expression of [125I]Sar1,Ile8-AII binding sites in the atria of neonatal Wistar Kyoto rats which were predominantly of the AT2 subtype. Atrial and ventricular cells, isolated from neonatal rat hearts and maintained for 3 days in culture demonstrated primarily AT1 binding sites. Stimulation of cultured atrial cells with AII resulted in an increase in inositol phosphate turnover and in intracellular calcium. The latter action was completely abolished by Losartan. Finally, in atria isolated from 2-month-old rats, AII produced a 17-19% increase in contractile force that was completely abolished by Losartan but not by PD 123319, thus indicating the presence of functional AT1 receptors.
J Mol Cell Cardiol 1993 Nov
PMID:Angiotensin II receptor subtypes and biological responses in the rat heart. 830 69

Angiotensin II acts as a cardiac growth factor, and causes both inotropic and chronotropic changes within the heart. In the present study, we used an in oculo model system to examine the effects of sympathetic innervation on the density of cardiac angiotensin II receptors. Quantitative autoradiography was used to determine the density of angiotensin II receptors in embryonic rat hearts grafted into either sympathetically innervated or sympathetically denervated eye chambers of adult host rats. The density of specific binding to angiotensin II receptors was nearly three-fold higher in sympathetically non-innervated compared to sympathetically innervated heart grafts (30.8 +/- 4.2 v 11.5 +/- 3.2 fmol/mg protein). Specific binding to angiotensin II receptors in heart grafts was displaced by addition of the AT1 receptor antagonist losartan, but not by addition of the AT2 receptor competitor PD 123177. Thus, only AT1 receptors were present in sympathetically innervated and sympathetically non-innervated embryonic rat hearts grafted in oculo. We conclude that changes in sympathetic innervation caused changes in the density of cardiac angiotensin II receptors in the present study. Our results may have implications for growth and function not only during cardiac development, but also during cardiac disease.
J Mol Cell Cardiol 1995 Nov
PMID:Sympathetic innervation modulates the expression of angiotensin II receptors in embryonic rat heart grafted in oculo. 859 95

The intrarenal renin-angiotensin system (RAS) contributes to the increased renal vascular resistance and reactivity observed in spontaneously hypertensive rats (SHR) and to the pathogenesis of high blood pressure (BP). Thus, we decided to characterize angiotensin II (ANG II) receptors in the renal arteries and glomeruli of 16-week-old SHR and their age-matched, normotensive Wistar-Kyoto (WKY) controls. SHR had significantly higher BP (153 +/- 4 v 96 +/- 10 mmHg) and heart weight (440 +/- 5 v 327 +/- 4 g/100 g body weight) than WKY rats. There was no difference in plasma renin activity between strains. Radioligand binding assays using non-peptide antagonists for AT1 (losartan) and AT2 (PD 123319) showed that renal preglomerular microvessels and glomeruli expressed a single receptor population (AT1) for ANG II. AT1 density tended to be lower in glomeruli of SHR compared to WKY (377 +/- 45 v 555 +/- 74 fmol/mg protein), but was significantly higher in preglomerular vessels (93 +/- 7 v 57 +/- 1 fmol/mg protein). No difference in receptor affinity was found in either preparation. Isolated kidney perfusion revealed that at low flow (3-10 ml/min), perfusion pressure was similar in both strains; however, at higher flow levels, SHR showed higher reactivity and less compliance than their controls. In addition, SHR presented a higher renal vascular reactivity to ANG II (but not to arterenol) than WKY rats. Thus, upregulation of ANG II receptors in the renal vasculature may mediate the hyperreactivity to ANG II observed in SHR kidney.
J Mol Cell Cardiol 1996 Feb
PMID:Characterization and hemodynamic implications of renal vascular angiotensin II receptors in SHR. 872 67

The plasma and cardiac renin-angiotensin systems may be activated after myocardial infarction. The myocardium may therefore be exposed to increased concentrations of angiotension II, which may contribute to myocardial injury. The purpose of this study was to identify the potential sites of action of angiotensin II in the infarcted heart. Myocardial infarction was induced in rats by left coronary artery ligation, and the hearts were removed for study after 18 h, 7 days, or 8 months. The regional ventricular angiotensin II receptor density was assessed by [125I](Sar1,Ile8)angiotensin II binding and quantitative autoradiography. The [125I](Sar1,Ile8)angiotensin II binding was unchanged at 18 h, but was increased at 7 days in the infarcted region of the left ventricle (73.2 +/- 3.2 amol/mm2, mean +/- S.E.M.) compared with the non-infarcted region (1.6 +/- 0.2 amol/mm2, P < 0.0001) and with the left ventricular myocardium of sham-operated control animals (1.3 +/- 0.1 amol/mm2, P < 0.0001). The increased [125I](Sar1,Ile8)angiotensin II binding density was still present, but diminished, at 8 months after coronary ligation (49.0 +/- 5.7 amol/mm2, P < 0.0001 v control, P = 0.0058 v 7-day infarcts). The increased binding of [125I](Sar1,Ile8)angiotensin II was antagonised by losartan, an AT1 receptor antagonist, but not by an AT2 receptor antagonist. Microautoradiography of [125I](Sar1,Ile8) angiotensin II, and assessment of collagen deposition using picrosirius staining and immunostaining demonstrated that the regional increase in AT1 receptor density in the infarcted region of myocardium was associated with fibroblast infiltration and collagen deposition. The infarct scar and the cardiac fibroblasts within it express high levels of angiotension II receptors and therefore represent potential targets for the actions of angiotensin II after myocardial infarction.
J Mol Cell Cardiol 1996 Feb
PMID:Regional changes in angiotensin II receptor density after experimental myocardial infarction. 872 73


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